The goal of this Phase I clinical trial will be to document safety and potential usefulness of 4- demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in combination with de-escalating doses of whole brain radiation therapy (WBRT), as binary therapy in subjects with advanced cancer involving the CNS [a Phase I clinical trial]. DM-CHOC-PEN is a polychlorinated pyridyl cholesteryloxycarbonate, which has completed Phase I/II clinical trials in adults with advanced cancer involving the CNS. Objective responses, improved PFS/OS and acceptable toxicities have been observed primarily in lung and breast cancers, melanoma and sarcoma malignancies involving the CNS. The incidence of metastatic cancer involving the CNS was >220,000 cases in the US alone in 2015, >20 times the incidence of high grade GBM. The four most common tumor types to develop CNS metastases were lung > breast > melanoma > renal cell ? 1,2,3,4, with median survival worse than those reported for primary CNS malignancies ? 8 months vs. 13 months for GBM. Radiation (RT) is still the main stay of treatment in the manage of CNS metastases since the presentation is often multi-focal, surgery is not attempted and most chemotherapeutic agents do not cross the blood brain barrier (BBB). However, responses to whole brain radiation (WBRT) and stereotactic radiosurgery (SRS) [standard of care] are of a short interval and associated with CNS side effects. Todate, the responses, tolerance and safety observed in those subjects with cancers involving the CNS that were treated with the drug, support the use of the proposed combination. DM-CHOC- PEN, an alkylating agent may also prevent DNA repair plus sensitize micrometasteses to radiation. Five (5) subjects ? 4-NSCLC and 1-sarcoma involving the CNS from the Phase I/II trials received radiation (RT) post-DM-CHOC-PEN therapy without toxicity; 1-subject (NSCLC) was treated twice and now a CR; all have had excellent long term responses. Plus, support is presented that the drug accumulates in cancers involving the CNS, as well as potentiates radiation effects in human lung cancer. A critical component in designing an agent to cross the protective BBB is selecting one that will be readily transported intracerebrally, does not produce local irritation and is not rejected back into the general circulation. DM-CHOC-PEN satisfies these requires - penetrates the BBB, plus is not a substrate for the transporter protein P-glycoprotein (P-gp) and not recycled out of the CNS. No neuropsycho-performance alterations or neuro-adverse events have been attributed to the drug in either the animal studies, or in any of the adult subjects treated. DM-CHOC-PEN?s MOA is via bis-alkylation of DNA [forms adducts with N7- guanine and N4 - cytosine] with no hematological/renal toxicities observed, thus the combination should be compatible, however will be monitored closely. The specific objectives of the Phase I study will be to: 1) Conduct a Phase I clinical trial with the binary combination - DM-CHOC-PEN plus de-escalating doses of WBRT, in adults with advanced cancer involving the CNS to document safety, toxicities, define acceptable minimal effective doses (MED) for the WBRT. 2) Study the pharmacokinetic/dynamic profiles for DM-CHOC-PEN and metabolites in the presence of WBRT in adults with advanced NSCLC adenocarcinoma involving the CNS. 3) Monitor and document any anticancer activity for the binary therapy; analyze data and prepare a binary Phase II clinical trial in subjects with cancers involving the CNS [IND - 68.876]. Drs. T Mahmood, P Friedlander, RS Weiner, M Barnhill, MH Hayman, ML Ware, E Zakris and M Mehta will be the coop-clinical trial center directors. They are well-established clinical investigators, a combination of medical, radiation and neuro-oncologists, most of whom were involved in the Phase I/IItrials with DM-CHOC-PEN and are well qualified to co-direct this binary trial. Consultants are identified in the Relevant Experience Section. Plus, the FDA supports the proposed Phase I binary study.